B lineage expression of the 67 kDa pan-T cell antigen, CD5, was first detected on the surface of certain human and murine malignancies 30 years ago and was subsequently identified on a subset of normal B cells in both species (reviewed in (Hardy and Hayakawa, 2001; Kantor and Herzenberg, 1993; Morris and Rothstein, 1994)). In mice, CD5 expression identifies a distinct B cell lineage, termed B1, that manifests unique ontologic, anatomic, and functional characteristics. In contrast to conventional B2 cells, murine B1 cells derive from CD19+ B220− progenitors, appear early in development, and preferentially locate to coelomic cavities (reviewed in (Berland and Wortis, 2002; Dorshkind and Montecino-Rodriguez, 2007; Herzenberg, 2000; Rothstein, 2002)). Most importantly, B1 cells differ functionally from B2 cells by spontaneously secreting “natural” immunoglobulin that is generated in the absence of specific immunization and which accounts for most of the resting IgM, and a large portion of the resting IgA, found in normal serum (Forster and Rajewsky, 1987; Ishida et al., 1992; Kroese et al., 1993; Sidman et al., 1986). This B1 cell-derived natural immunoglobulin differs from B2 cell-derived antibody in being more germline like (as a result of minimal N-region addition and somatic hypermutation), and is broadly reactive and repertoire-selected (Forster et al., 1988; Gu et al., 1990; Hardy et al., 1989; Pennell et al., 1989).
Natural immunoglobulin is vitally important in the early defense against bacterial and viral infections (Baumgarth et al., 2000; Boes et al., 1998; Briles et al., 1981; Haas et al., 2005; Ochsenbein et al., 1999), and may play a role in a wide variety of diseases, through recognition of self-antigens and binding of cellular debris (Binder and Silverman, 2005). In addition, B1 cells differ functionally from B2 cells in efficiently presenting antigen to T cells (Zhong et al., 2007), and in displaying evidence of tonic signaling (Holodick et al., 2009b; Karras et al., 1997; Wong et al., 2002), in the “resting” state in the absence of specific stimulation. Whereas B1 cells have been considered to be self-renewing and thus self-perpetuating in adult animals (Hayakawa et al., 1986; Kantor et al., 1995), recent evidence suggests that new bone marrow emigrants are continually added to the B1 cell pool (Holodick et al., 2009a).
A subpopulation of CD5-expressing B cells is found in various human tissues, and the number of such CD5+ B cells is expanded in some autoimmune diseases (Burastero et al., 1988; Dauphinee et al., 1988; Plater-Zyberk et al., 1985; Taniguchi et al., 1987). The significance of this is uncertain, however, because it is not clear that CD5 is a durable marker of the B1 cell population across species. Not only is CD5 expressed on B2 cell populations in the human system (including transitional, pre-naive and activated B cells), but in other mammals CD5 is nondiscriminatory (Freedman et al., 1989; Lee et al., 2009; Raman and Knight, 1992; Sims et al., 2005; Wilson and Wilkie, 2007). As a result there has been much controversy regarding whether B1 cells exist at all in Homo sapiens, and if so, how human B1 cells might be characterized. Resolution of this problem is of great importance, because a full understanding of the relationship between B1 cells and diseases ranging from autoimmune dyscrasias to lymphoid malignancies depends on elucidating identifying features that will allow human B1 cells to be readily enumerated and functionally evaluated in clinical situations.